B-cell numbers in the blood of patients with non-HLA*B8 or non-HLA*B44 common variable immunodeficiency.

BACKGROUND: Genetic susceptibility to common variable immunodeficiency (CVID) has been linked to the inheritance of part or all of 2 extended major histocompatibility complex haplotypes: HLA*B8*DR3(17) and HLA*B44*DR7. OBJECTIVE: To determine whether the inheritance of these major histocompatibility complex susceptibility haplotypes correlates with absolute B-cell numbers. METHODS: A retrospective medical record review of 55 consecutive patients with CVID whose blood was analyzed for B-cell numbers using a fluorescent-activated cell sorter. RESULTS: The mean +/- SD absolute count of CD19+ B cells among the 36 patients (65%) with CVID who had inherited HLA*B8 or HLA*B44 was 218 +/- 23 cells/mm3 compared with 119 +/- 27 cells/mm3 in those who had not inherited HLA*B8 or HLA*B44 (P = .008). There were no significant differences in B-cell numbers among the 33 patients (60%) with CVID who had inherited HLA*DR7 or HLA*DR3(17) and those who had not. CONCLUSIONS: Patients with CVID who inherited HLA*B44 or HLA*B8 tended to have higher numbers of B cells in the blood than those who did not, suggesting that the mechanism of immunodeficiency may differ.     

The future of children is now

A community resource network, Annie Sullivan Enterprises, Inc., is described as a system for community integration of children and youth who have developmental disabilities and mental health problems. A brokerage model is espoused for accessing and delivering services. The model is based on Hobb's (1975) view that organization of human services must be based primarily on the client's needs rather than on the needs of the service agency. Lessons and recommendations based upon 7 years of successful operation are described.Adaptation of a paper presented at Nicholas Hobbs Award Ceremony, 97th annual meeting of the American Psychological Association, New Orleans, Lousiana, August 12, 1989. We acknowledge MCH Project #922 and ADD #24882 for support during the writing of this report.     

Measurement of cerebral blood flow by intravenous xenon-133 technique and a mobile system. Reproducibility using the Obrist model compared to total curve analysis

The recent development of a mobile 10 detector unit, using i.v. Xenon-133 technique, has made it possible to perform repeated bedside measurements of cerebral blood flow (CBF). Test-retest studies were carried out in 38 atherosclerotic subjects, in order to evaluate the reproducibility of CBF level and side-to-side asymmetry. Data were analysed according to the Obrist model and the results compared with those obtained using a model correcting for the air passage artifact. Reproducibility was of the same order of magnitude as reported using stationary equipment. The side-to-side CBF asymmetry was considerably more reproducible than CBF level. Using a single detector instead of five regional values averaged as the hemispheric flow increased standard deviation of CBF level by 10-20%, while the variation in asymmetry was doubled. In optimal measuring conditions the two models revealed no significant differences, but in low flow situations the artifact model yielded significantly more stable results. The present apparatus, equipped with 3-5 detectors covering each hemisphere, offers the opportunity of performing serial CBF measurements in situations not otherwise feasible.     

Determination of the proliferative fraction of a transplantable, hormone-dependent, human prostatic carcinoma (PC-82) by monoclonal antibody Ki-67: potential application for hormone therapy monitoring

The transplantable, hormone-dependent, human prostatic carcinoma PC-82 was used as an in vivo model for monitoring the proliferative fraction of tumor cells under the influence of androgen withdrawal and resubstitution. The number of cycling cells was assessed by means of an immunoperoxidase method and monoclonal antibody Ki-67. The number of Ki-67-positive tumor cells dropped from an average of 17% in androgen-supplemented, tumor-bearing female BALB/c mice to approximately 1.0% within 10 days after removal of the testosterone (T) implant. A similar effect was noted after castration of tumor-bearing male BALB/c mice. Androgen resubstitution after a 10-day period of T deprivation resulted in a rise in the tumor cell proliferation index to 20% within 4 days. The same pattern of response to androgen depletion and resubstitution also was found when the number of cycling cells in S phase was assessed by the 5-bromo-2'-deoxyuridine incorporation technique. Administration of supraphysiologic doses of T in intact male mice did not lead to an increase in the number of Ki-67-stained nuclei. Androgen manipulation did not influence the immunohistochemically assessed expression of prostatic acid phosphatase and prostate-specific antigen. The rapid effect of hormone deprivation and resubstitution in the tumor cell proliferation fraction suggests that monoclonal antibody Ki-67 can be used for monitoring the short-term effects of hormonal treatment of prostatic cancer.     

Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.

PURPOSE: To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma. EXPERIMENTAL DESIGN: Four hundred patients with the following disorders were studied: MGUS (76 patients); smoldering (indolent; early-stage) multiple myeloma (SMM; 112 patients); newly diagnosed, active multiple myeloma (MM; 99 patients); relapsed (advanced) multiple myeloma (RMM; 26 patients); and primary amyloidosis (AL; 87 patients). Forty-two normal control BM samples were studied for comparison. BM angiogenesis was studied in a blinded manner by immunohistochemical staining for CD34 to identify microvessels. RESULTS: The median (range) microvessel density (MVD) per x400 high power field was 1.3 (0-11) in the controls, 1.7 (0-10) in AL, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in newly diagnosed MM, and 20 (6-47) in RMM; P < 0.001. MVD was significantly higher in MGUS, SMM, newly diagnosed MM, and RMM compared with controls and AL; P < 0.001. MVD was not significantly different between controls and AL. By grading, high-grade angiogenesis was present in 0% of controls and AL, 1% of MGUS, 3% of SMM, 29% of newly diagnosed MM, and 42% of RMM; P < 0.001. MVD correlated with the BM plasma cell labeling index (rho = 0.46, P < 0.001) and BM plasma cell percentage (rho 0.5, P < 0.001). Survival was 28 months in SMM and newly diagnosed MM with high-grade angiogenesis, compared with 53 months for those with low- and intermediate-grade angiogenesis; P = 0.02. CONCLUSIONS: BM angiogenesis progressively increases along the spectrum of plasma cell disorders, from the more benign MGUS stage to advanced myeloma, indicating that angiogenesis may be related to disease progression.     

Enhancement of Cu bioavailability in the rat by phytic acid

The objective of this study was to evaluate the effect of phytic acid on copper (Cu) bioavailability. Male weanling rats were fed a Cu-deficient diet (less than 1.0 micrograms/g) for 4 wk and then were divided into 12 groups (n = 8) in a factorial design. Cu-deficient rats were then fed diets containing 1.4, 3.0, 5.2 or 10.5 micrograms Cu/g (CuCO3) and 0, 0.4 or 0.8% phytic acid as sodium phytate at each Cu level. All diets contained 30 micrograms Zn/g. After 3 d of Cu repletion, liver copper (LCu), liver Cu-Zn superoxide dismutase (LSOD) activity, serum Cu (SCu) and serum ceruloplasmin (CP) concentrations were determined. These parameters were used as indexes of Cu bioavailability. The addition of phytic acid to diets fed to Cu-deficient rats significantly enhanced Cu bioavailability compared to that of rats fed diets without phytic acid. Coefficients of determination (r2) were calculated for each response parameter versus dietary Cu concentration. The r2-values for pooled LCu and LSOD values were 0.31 and 0.30, respectively, between 1.4 and 5.2 micrograms Cu/g. At low dietary Cu concentrations, liver Cu parameters (i.e., LCu and LSOD) were more responsive indexes of Cu status than SCu and CP. Each index of Cu status was found to correlate with the other indexes of Cu nutriture. Phytic acid is postulated to enhance Cu utilization by its ability to bind other dietary components, such as Zn, that compete with Cu at the site of intestinal absorption.     

Dihydroorotase catalyzes the ring opening of the hydrolysis intermediates of the cardioprotective drug dexrazoxane (ICRF-187).

The enzyme kinetics of the hydrolysis of the one-ring open metabolites of the antioxidant cardioprotective agent dexrazoxane [ICRF-187; (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane] to its active metal ion binding form ADR-925 [N,N'-[(1S)-1-methyl-1,2-ethanediyl]bis[N-(2-amino-2-oxoethyl)glycine] by dihydroorotase (DHOase) has been investigated by high-performance liquid chromatography (HPLC). A spectrophotometric detection HPLC assay for dihydroorotate was also developed. Dexrazoxane is clinically used to reduce the iron-based oxygen free radical-mediated cardiotoxicity of the anticancer drug doxorubicin. DHOase was found to catalyze the ring opening of the metabolites with an apparent V(max) that was 11- and 27-fold greater than its natural substrate dihydroorotate. However, the apparent K(m) for the metabolites was 240- and 550-fold larger than for dihydroorotate. This report is the first that DHOase might be involved in the metabolism of a drug. Furosemide inhibited DHOase, but the neutral 4-chlorobenzenesulfonamide did not. Because dihydroorotate, the one-ring open metabolites, and furosemide all have a carboxylate group, it was concluded that a negative charge on the substrate strengthened binding to the positively charged active site. The presence of DHOase in the heart may explain the cardioprotective effect of dexrazoxane. Thus, dihydropyrimidinase and DHOase acting in succession on dexrazoxane and its metabolites to form ADR-925 provide a mechanism by which dexrazoxane is activated to exert its cardioprotective effects. The ADR-925 thus formed may either remove iron from the iron-doxorubicin complex, or bind free iron, thus preventing oxygen radical formation.